核小体
组蛋白八聚体
组蛋白
组蛋白H3
连接器DNA
化学
组蛋白密码
染色体
生物物理学
细胞生物学
组蛋白甲基化
乙酰化
生物化学
DNA
生物
DNA甲基化
基因表达
基因
作者
Ekaterina Smirnova,Emmanuelle Bignon,Patrick Schultz,Gábor Pápai,Adam Ben-Shem
标识
DOI:10.7554/elife.87989.3
摘要
Sirtuin 6 (SIRT6) is an NAD+ dependent histone H3 deacetylase that is prominently found associated with chromatin, attenuates transcriptionally active promoters and regulates DNA repair, metabolic homeostasis and lifespan. Unlike other sirtuins, it has low affinity to free histone tails but demonstrates strong binding to nucleosomes. It is poorly understood how SIRT6 docking on nucleosomes stimulates its histone deacetylation activity. Here we present the structure of human SIRT6 bound to a nucleosome determined by cryogenic electron microscopy. The zinc finger domain of SIRT6 associates tightly with the acidic patch of the nucleosome through multiple arginine anchors. The Rossmann fold domain binds to the terminus of the looser DNA half of the nucleosome, detaching two turns of the DNA from the histone octamer and placing the NAD+ binding pocket close to the DNA exit site. This domain shows flexibility with respect to the fixed zinc finger and moves with, but also relative to, the unwrapped DNA terminus. We apply molecular dynamics simulations of the histone tails in the nucleosome to show that in this mode of interaction, the active site of SIRT6 is perfectly poised to catalyze deacetylation of the H3 histone tail and that the partial unwrapping of the DNA allows even lysines close to the H3 core to reach the enzyme.
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